Abstract
A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
Highlights
Infliximab is a chimeric monoclonal antibody blocking the effect of tumor necrosis factor alpha (TNF-α) which has been widely used since 1999 for treatment of a number of inflammatory rheumatic diseases including rheumatoid arthritis (RA)
It reached a stable range with a mean of 1.8 μg/mL [standard deviation (SD) of 2.0 μg/mL] from week 14 when infusions were 8 weeks apart (Figure 1)
To determine an optimal serum trough infliximab (sIFX) level defined as the range of trough levels that had the sensitivity and specificity to predict good EULAR response, Receiver Operating Characteristic (ROC) curves where done for both the cross-sectional cohort and the prospective cohort (Figure 2)
Summary
Infliximab is a chimeric monoclonal antibody (mAb) blocking the effect of tumor necrosis factor alpha (TNF-α) which has been widely used since 1999 for treatment of a number of inflammatory rheumatic diseases including rheumatoid arthritis (RA). TNF-α inhibitors (TNFi) were the first monoclonal antibody therapy shown to significantly halt progression of these diseases in clinical trials [1,2,3], and the treatment effect is even more efficient in combination with other disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) [3]. Up to 40% of patients do not respond to TNFi treatment according to the EULAR (European League Against Rheumatism) response criteria [4,5,6,7]. These patients can be categorized into those who never achieve any response (primary treatment failure), and those who lose response over time (secondary treatment failure) [8].
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